Human Immunodeficiency Virus Type 1 (HIV-1) infects CD4-positive T cells and monocytes/macrophages and cause Acquired Immune Deficiency Syndrome (AIDS) in humans. Research proposed in this application is focusing on the cellular factors that resist HIV-1 infection that are activated immediately after HIV enters cells. These proteins are cellular cytidine deaminases (called APOBEC proteins) that convert cytosines to uracils on genomic targets and play important roles in protein metabolism and immune responses. The critical factor for our study is the recent finding that APOBEC3 proteins modify HIV-1 viral genomes and thus block their replication. This potent protective mechanism is circumvented by HIV-1 (and other primate lentiviruses) by their production of a viral infectivity factor, Vif. Vif renders the APOBEC3 proteins inactive and thus allows viral infection. These exciting discoveries have uncovered a fierce battlefield between retroviruses and intracellular immune networks. At the same time, these interactions provide for a unique and novel opportunity to exploit APOBEC3 proteins as new tools for anti-HIV therapeutics. Our long-term objective is to develop successful therapeutic treatments for HIV-1 by overcoming the vulnerability of this innate immunity to viral protein Vif. This proposal will address three specific aims: (1) To study the molecular structure of this antiviral innate immunity and identify additional APOBEC3 family members;(2) To study the enzymatic complex of APOBEC3 proteins and determine the cellular cofactors present in the putative editosome;(3) To define the precise mechanism by which Vif disrupts this innate intracellular immunity by binding to and destroying APOBEC3s. This project will lead to a definition of the architecture of this innate immune system, and will also lead to a full understanding of the antiviral mechanism during infection. Importantly, we will identify the molecular determinant(s) usurped by Vif to counteract this immunity. New therapeutic targets will be discovered to help us repair the vulnerable aspect of this immunity so it can constitutively function during HIV infection. Such findings may provide a more effective modality for the treatment of HIV infection to be used in conjunction with other chemotherapy and vaccines.